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expert reaction to mouse study of gene therapy for Alzheimer’s disease

A group of scientists have described their use of a specific gene therapy to treat Alzheimer’s disease in a mouse model. Publishing in the journal Proceedings of the National Academy of Sciences the scientists report that the upregulation of the PGC-1α gene brought about reduced biological markers of the disease and improved function in the mice.


Prof. Alan Boyd, President of the Faculty of Pharmaceutical Medicine, said:

“Alzheimer’s disease is a devastating illness both for patients and their families, but so far it is only possible to treat some of the symptoms of the disease and a treatment has not yet been identified that aims to attack the underlying disease process and halt the progression of the disease itself, which may result in a cure. Several approaches have been tried previously but without success. It is therefore vital that a treatment is identified that does modify the disease process.

“Using gene therapy might be a route to help with this problem. The gene therapy that has been used in this study in mice, which are a model for Alzheimer’s disease in humans, produces an enzyme that is known to be decreased in patients with the disease. Replacing this missing enzyme via the administration of the gene therapy within the brain is thought to help stop the build-up of the amyloid plaques in the brain that occur in Alzheimer’s disease.

“The use of gene therapies to treat diseases has been developed over the past twenty-five years or so and there are now three gene therapies that are now available as prescription medicines. To date, around fifty clinical studies in humans have been conducted that involve using gene therapies to treat diseases in the brain and the nervous system. The most notable of these have been in the treatment of Parkinson’s disease. So this shows that it could be possible to use the gene therapy approach to treat Alzheimer’s disease too.

“However, although the study that has been reported in the article is showing a promising result, much more work needs to be done before it could be used in a clinical study in patients with Alzheimer’s disease. This will take between two to three years and will include the manufacture of the gene therapy to standards that will allow it to be administered to humans and more animal studies to further assess the safety and distribution of the gene therapy product. Given the nature of the disease and the difficulties that have been encountered in finding treatments that will stop the progression of this terrible disease, this approach is a step in the right direction and should be encouraged and supported.”


Dr Mark Dallas, Lecturer in Cellular and Molecular Neuroscience, University of Reading, said:

“This study looked at the potential of using gene therapy to combat Alzheimer’s disease in a mouse model. Whilst providing some good scientific evidence to demonstrate a reduction in the levels of a toxic protein that contributes to the disease, we cannot yet call it a break through moment which is of immediate value to people with dementia.

“Mice do not develop Alzheimer’s disease and scientists commonly use mice that have been genetically altered to develop the disease in their research. This is a common limitation when scientists are investigating new drugs to treat dementia.’

“Gene therapy has a chequered history and therefore it will need to be tested more extensively before we can exploit the potential of gene therapy for Alzheimer’s disease.”


Dr Tara Spires-Jones, Interim Director, Centre for Cognitive and Neural Systems, University of Edinburgh, said:

“This study from Sastre’s group at Imperial College London demonstrates that gene therapy using a virus injected into the brain to boost levels of a helpful molecule is beneficial in one model of early Alzheimer’s disease. While scientifically interesting, this study should be interpreted with caution as the results are based on very few mice (around 5-10 per group) in only one model of the disease. These results will need to be replicated in multiple models and many hurdles overcome to know whether this type of treatment will be useful for human patients.”


Prof. Rob Howard, Professor of Old Age Psychiatry, UCL, said:

“In terms of identifying a potential mechanism for the treatment of people with Alzheimer’s disease, this work looks promising. However, it is really important to remember that APP23 transgenic mice do not really have Alzheimer’s disease. They have a simple over-production of beta-amyloid in their brains, whereas Alzheimer’s disease patients have other pathology, such as neurofibrillary tangles, which are considered diagnostic.

“This work should best be viewed as demonstrating proof of concept in blocking the development of one aspect of the brain pathology seen in Alzheimer’s disease, within a genetically modified animal model. This may or may not translate into benefits when applied to humans, but is an important first step. Before clinical effectiveness trials of this technology in Alzheimer patients can be conducted, I would anticipate several years of early phase and safety studies. Only time will tell.

“As for so many of these promising technologies, we will only be able to judge the utility of the approach and potential benefits to patients and their families after conduct of successful clinical trials.”


Prof. John Hardy, Professor of Neuroscience, UCL, said:

“While this is an interesting study, it should be borne in mind that in Alzheimer’s disease there is massive neuronal loss which underlies the clinical symptoms, but in these mouse models there is very little cell loss and the clinical deficits in the mice are different from those in humans with the disease.  So extrapolation from the mouse work in this instance is a stretch.  However, we know inflammation is part of the problem in Alzheimer’s disease, and if this approach reduces the inflammatory processes in the disease it may suggests a novel approach to therapy.”


Dr Doug Brown, Director of Research and Development, Alzheimer’s Society, said:

“This research takes a new approach to tackling the underlying causes of Alzheimer’s disease – using a technique called gene therapy to interrupt the production of amyloid protein, one of the key hallmarks of Alzheimer’s. So far, potential treatments that directly target amyloid build-ups in the brain have mostly had disappointing results in clinical trials, whereas this study could pave the way for a new plan of attack.

“It’s still early days for this gene therapy approach – while it has shown promise in mice, we’re still not sure whether this will be suitable for people. Using gene therapy could prove to be useful further down the line in dementia research and we look forward to seeing if this will be an effective way of developing future treatments.”


Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK, said:

“There are currently no treatments able to halt the progression of damage in Alzheimer’s, so studies like this are important for highlighting new and innovative approaches to take us towards that goal. This research sets a foundation for exploring gene therapy as a treatment strategy for Alzheimer’s disease, but further studies are needed to establish whether gene therapy would be safe, effective and practical to use in people with the disease. The findings support PGC-1-alpha as a potential target for the development of new medicines, which is a promising step on the road towards developing treatments for this devastating condition.”


‘PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model’ by Katsouri et al. published in Proceedings of the National Academy of Sciences (PNAS) on Monday 10th October. 


Declared interests

Dr Spires-Jones: No conflicts of interest to declare.

Prof. Hardy: Consulting for Ceracuity and Eisai

All others: None received

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